Anorexia nervosa (AN) is a devastating neuropsychiatric disease with a high prevalence (up to 2.2% ofwomen) and significant morbidity and mortality. There are currently no effective therapeutic agents for thedisorder. The goal of Courage Therapeutics is the development of melanocortin-3 receptor (MC3R) -specificagonist peptides for the treatment of anorexia nervosa. The product of this Phase I STTR will be a patentableMC3R agonist lead development candidate that can go into advanced animal testing and ADME/PK fordevelopment of a therapeutic for anorexia nervosa, during a Phase II STTR. In preliminary results presentedhere, we show that MC3R is expressed in nearly all AgRP neurons in the arcuate nucleus. Activation of theseMC3R-expressing neurons in the arcuate can stimulate food intake while reducing anxiety. Further, wedemonstrate that administration of a MC3R-specific peptide results in potent stimulation of food intake in micethat is AgRP neuron dependent. Melanocortin peptide drugs appear to be safe and effective therapeutics for anumber of other indications, however no MC3R specific therapeutics have been developed. Based on thesedata, we propose that MC3R-specific agonist peptides may be developed into safe and effective therapeutics foreating disorders such as anorexia nervosa. We have identified four promising MC3R agonist starting points,including both D-Trp8-ï§-MSH and Ac-Arg-Arg-D-Phe(4-I)-D-Tic-NH2 as exemplary parent leads that potentlystimulate food intake in sated animals. In one aim of this application, Courage Therapeutics will designanalogues based on these two MC3R-specific agonists as promising linear peptides to improve their overallpotency, efficacy, and receptor-subtype specificity. Courage will also conduct similar studies on two cyclicmelanocortin peptides lacking receptor specificity, related to Setmelanotide (Rhythm), which has been highlysuccessful in clinical trials for the treatment of syndromic obesity. In this case, the starting peptides arealready known to have drug-like properties, and the chemical goal will be engineer MC3R-specificity in thischemical class of melanocortin peptides. In Aim 2, peptides with appropriate pharmacological properties (EC50below 10nM, Emax>50%, and a 1000x MC3R/MC4R agonist specificity) will be modified to improve stabilityand bioavailability. Peptides will then be tested for in vivo efficacy on feeding, weight gain, and anxiety in bothnormal animals and a model of stress-induced anorexia. Peptides will also be tested for half life anddistribution in vivo in serum and brain. The product of this Phase I STTR will be patentable MC3R agonist leaddevelopment candidates that can go into advance preclinical testing and full ADME/PK and safety fordevelopment of a therapeutic for AN, to be completed under Phase II of this application. A clinical trial for thesuccessful development candidate would then test effectiveness in a placebo controlled randomized study forfemale Restricting Anorexia Nervosa in post-acute hospitalization recovery. Primary trial end-points wouldinclude time to achieve weight restoration, meal completion, improvement of self reported EDE-Q (EatingDisorder Examination Questionnaire) and related self-reported eating attitude scores. Anorexia nervosa is a devastating neuropsychiatric disease with a high prevalence (up to 2.2% of women) and
significant morbidity and mortality. There are currently no effective therapeutic agents for the disorder. The
product of this Phase I STTR will be patentable MC3R agonist lead development candidates that can go into
advanced animal testing and ADME/PK for development of a therapeutic for anorexia nervosa. Adipose tissue ; Fatty Tissue ; adipose ; white adipose tissue ; yellow adipose tissue ; Animals ; Anorexia ; Anorexia Nervosa ; Anxiety ; Structure of nucleus infundibularis hypothalami ; Arcuate Nucleus ; Infundibular Nucleus ; Attitude ; Automobile Driving ; driving ; Mental disorders ; Mental health disorders ; Psychiatric Disease ; Psychiatric Disorder ; mental illness ; psychiatric illness ; psychological disorder ; Biological Availability ; Bioavailability ; Biologic Availability ; Physiologic Availability ; Body Image ; body perception ; Brain ; Brain Nervous System ; Encephalon ; Clinical Trials ; Cyclization ; Disease ; Disorder ; Pharmaceutical Preparations ; Drugs ; Medication ; Pharmaceutic Preparations ; drug/agent ; Eating ; Food Intake ; Eating Disorders ; Engineering ; Exhibits ; Fright ; Fear ; Female ; gamma-Aminobutyric Acid ; 4-Aminobutanoic Acid ; 4-Aminobutyric Acid ; 4-amino-butanoic acid ; Aminalon ; Aminalone ; GABA ; γ-Aminobutyric Acid ; Gastric Emptying ; stomach emptying ; Goals ; Half-Life ; Hospitalization ; Hospital Admission ; Hospitals ; Hypoactive Sexual Desire Disorder ; In Vitro ; Lead ; Pb element ; heavy metal Pb ; heavy metal lead ; men ; men's ; Morbidity - disease rate ; Morbidity ; mortality ; Motivation ; Mus ; Mice ; Mice Mammals ; Murine ; Neurobiology ; neurobiological ; Neurons ; Nerve Cells ; Nerve Unit ; Neural Cell ; Neurocyte ; neuronal ; Obesity ; adiposity ; corpulence ; Parents ; Patients ; Peptides ; Periodicity ; Cyclicity ; Rhythmicity ; Drug Kinetics ; Pharmacokinetics ; Pharmacology ; Puberty ; Questionnaires ; Rewards ; Safety ; Satiation ; satiety ; Specificity ; Stress ; Syndrome ; Testing ; Thinness ; Leanness ; Time ; Weight Gain ; Weight Increase ; body weight gain ; body weight increase ; wt gain ; Weight ; Woman ; Measures ; Data Set ; Dataset ; base ; improved ; Peripheral ; Acute ; Chronic ; Clinical ; Phase ; Series ; Age of Onset ; Peptide Receptor ; Chemicals ; Serum ; Blood Serum ; Recovery ; analog ; Funding ; Agonist ; Melanocortin 3 Receptor ; MC3 Receptor ; Receptor, Melanocortin, Type 3 ; metabolic abnormality assessment ; Abnormal Assessment of Metabolism ; Metabolic Studies ; Metabolism Studies ; Therapeutic ; Therapeutic Agents ; Metabolic ; subdermal ; subcutaneous ; peptide analog ; Protein Cleavage ; Proteolysis ; Receptor Protein ; receptor ; success ; sex dimorphism ; sexually dimorphic ; sexual dimorphism ; Arg-Arg ; arginyl-L-arginine ; arginylarginine ; novel ; Self-Report ; Patient Self-Report ; Modeling ; neuropsychiatric ; neuropsychiatry ; Property ; drug development ; ghrelin ; Causality ; causation ; disease causation ; Etiology ; MSH4 ; MutS Homolog 4 ; MSH4 gene ; Dose ; Animal Testing ; Data ; High Prevalence ; pre-clinical testing ; Preclinical Testing ; in vivo ; Clinical Treatment ; trial regimen ; trial treatment ; Small Business Technology Transfer Research ; STTR ; Pathologic ; trend ; Characteristics ; Modification ; Development ; developmental ; Behavioral ; pre-clinical ; preclinical ; genome wide association study ; GWA study ; GWAS ; genome wide association ; genome wide association scan ; genome wide association studies ; genomewide association scan ; genomewide association studies ; genomewide association study ; whole genome association analysis ; whole genome association studies ; whole genome association study ; feeding ; design ; designing ; Prevalence ; hedonic ; N-terminal ; NH2-terminal ; Resistance ; resistant ; presynaptic ; C-terminal ; FDA approved ; efficacy testing ; cognitive process ; behavioral study ; behavior study ; peptide drug ; therapeutic peptide ; neuropsychiatric disorder ; neuropsychiatric disease ; in vivo evaluation ; in vivo testing ; randomized placebo controlled study ; weight restoration ; afamelanotide ; Scenesse ; effectiveness testing ; therapeutically effective ;
